DESCRIPTION: Complex urethral defects from congenital and acquired abnormalities are often surgically managed with autologous tissue grafts in order to restore organ continuity. Unfortunately, these approaches are associated with severe adverse complications such as donor site morbidity, recurrent strictures, and stone formation. Silk fibroin (SF) biomaterials provide an exceptional combination of physical characteristics including high tensile strength and elasticity, diverse processing flexibility, and tunable degradability that are well suited to support urethral function. Therefore, these scaffolds may overcome the deleterious side-effects associated with conventional reconstructive techniques and serve as off-the-shelf grafts for urethral tissue repair. By understanding the role of the innate immune response in facilitating constructive remodeling of urethral defects, we will design instructive SF implants with selective micro environmental cues sufficient to promote activation of anti-inflammatory macrophage phenotypes (M2a and M2c) in order to achieve maximal regenerative outcomes. In this application, we will challenge the overall hypothesis that: acellular SF matrices promote macrophage- dependent constructive remodeling in urethroplasty. The specific aims of the application are: Specific Aim 1: Determine the impact of the innate immune response on scaffold mediated, constructive remodeling of urethral defects. Specific Aim 2: Develop tubular SF grafts for superior functional repair of urethral strictures.